Stabilized compositions of volatile alkylating agents and methods of using thereof

ABSTRACT

A composition and method for treatment of cancer. The composition for treating a skin disorder, comprising: a Nitrogen Mustard or an HX salt of the Nitrogen Mustard, wherein the Nitrogen Mustard or the HX salt of the Nitrogen Mustard is in a non-aqueous vehicle or carrier that does not include petrolatum or ethanol, wherein the non-aqueous vehicle or carrier that does not include petrolatum or ethanol does not include petrolatum or ethanol. The method comprises topically applying the composition of a Nitrogen Mustard or a HX salt of the Nitrogen Mustard to the affected skin, wherein the Nitrogen Mustard or the HX salt of the Nitrogen Mustard is in a non-aqueous vehicle or carrier that does not include petrolatum or ethanol, wherein the non-aqueous vehicle or carrier does not include petrolatum or ethanol.

The present patent application is a division of U.S. application Ser.No. 11/369,305, filed Mar. 7, 2006, which is a non-provisionalapplication claiming priority from provisional applications with S/Ns:60/661,356 (filed Mar. 14, 2005 and titled “Stabilized Compositions ofVolatile Alkylating Agents and Methods of Using Thereof”) and 60/751,128(filed Dec. 16, 2005 and also titled “Stabilized Compositions ofVolatile Alkylating Agents and Methods of Using Thereof”).

FIELD OF THE INVENTION

The present invention relates generally to a composition and method fortopical treatment of skin disease, and more specifically to a stabilizedNitrogen Mustard composition and method for topically treating the skindisease.

BACKGROUND

Cutaneous T-cell lymphoma (CTCL) is a malignancy of the T-helper (CD4+)cells of the immune system. CTCL, also known as mycosis fungoides (MF),is a cancer of the white blood cells that primarily affects the skin andonly secondarily affects other sites. This disease involves theuncontrolled proliferation of T-lymphocytes known as T-helper cells, sonamed because of their role in the immune response. T-helper cells arecharacterized by the presence of a protein receptor on their surfacecalled CD4. Accordingly, T-helper cells are said to be CD4+.

The proliferation of T-helper cells results in the penetration, orinfiltration, of these abnormal cells into the epidermal layer of theskin. The skin reacts with slightly scaling lesions that itch, althoughthe sites of greatest infiltration do not necessarily correspond to thesites of the lesions. The lesions are most often located on the trunk,but can be present on any part of the body. In the most common course ofthe disease, the patchy lesions progress to palpable plaques that aredeeper red and have more defined edges. As the disease worsens, skintumors develop that are often mushroom-shaped, hence the name mycosisfungoides. Finally, the cancer progresses to extracutanous involvement,often in the lymph nodes or the viscera.

CTCL is a rare disease, with an annual incidence of about 0.29 cases per100,000 persons in the United States. It is about half as common inEastern Europe. However, this discrepancy may be attributed to adiffering physician awareness of the disease rather than a truedifference in occurrence. In the Unites States, there are about 500-600new cases a year and about 100-200 deaths. CTCL is usually seen in olderadults; the median age at diagnosis is 55-60 years. It strikes twice asmany men as women. The average life expectancy at diagnosis is 7-10years, even without treatment.

The most common side effect for treatments applied to the skin is skinhypersensitivity to the drug. There is a need for improved compositionsand methods for skin diseases that avoid or minimize skinhypersensitivity to the drug.

SUMMARY OF THE INVENTION

A first aspect of the present invention provides a composition fortreating a skin disorder, comprising: a Nitrogen Mustard or an HX saltof the Nitrogen Mustard, wherein the Nitrogen Mustard or the HX salt ofthe Nitrogen Mustard is in a non-aqueous vehicle or carrier, wherein thenon-aqueous vehicle or carrier does not include petrolatum or ethanol,wherein the Nitrogen Mustard is represented by the following structures:

wherein each R₁, R₂, R₃ . . . R₃₄ (R₁-R₃₄) is independently selectedfrom the group consisting of a hydrogen atom, a linear alkyl grouphaving 1-6 carbon atoms, a branched alkyl group having 2-12 carbonatoms, a cycloalkyl group having 3-17 carbon atoms, a fluorinated linearalkyl group having 2-12 carbon atoms, a fluorinated branched alkyl grouphaving 2-12 carbon atoms, a fluorinated cycloalkyl group having 3-17carbon atoms, an aryl group, an aralkyl group, an alkaryl group, acycloalkyl group, a bicycloalkyl group, an alkenyl group, an alkalkenylgroup, an alkenylalkyl group, an alkynyl group, an alkalkynyl group, analkynylalkyl group, a trifluoropropyl group, a cyanopropyl group, anacryloyl group, an arylacryloyl group, an acryloylaryl group, analkylacyl group, an arylacyl group, an alkylenylacyl group, and analkynylacyl group, wherein n is 1, 2 or 3, wherein p is 0, 1 or 2,wherein n+p≦3, and wherein any two R₁-R₃₄ in the same molecule may belinked to form a three- to eight-membered cyclic group.

A second aspect of the present invention provides A method for treatinga person with a skin disorder, comprising: topically applying to theaffected skin a Nitrogen Mustard or an HX salt of the Nitrogen Mustard,wherein the Nitrogen Mustard or the HX salt of the Nitrogen Mustard isin a non-aqueous vehicle or carrier, wherein the non-aqueous vehicle orcarrier does not include petrolatum or ethanol, wherein the NitrogenMustard is represented by the following structures:

wherein each R₁, R₂, R₃ . . . R₃₄ (R₁-R₃₄) is independently selectedfrom the group consisting of a hydrogen atom, a linear alkyl grouphaving 1-6 carbon atoms, a branched alkyl group having 2-12 carbonatoms, a cycloalkyl group having 3-17 carbon atoms, a fluorinated linearalkyl group having 2-12 carbon atoms, a fluorinated branched alkyl grouphaving 2-12 carbon atoms, a fluorinated cycloalkyl group having 3-17carbon atoms, an aryl group, an aralkyl group, an alkaryl group, acycloalkyl group, a bicycloalkyl group, an alkenyl group, an alkalkenylgroup, an alkenylalkyl group, an alkynyl group, an alkalkynyl group, analkynylalkyl group, a trifluoropropyl group, a cyanopropyl group, anacryloyl group, an arylacryloyl group, an acryloylaryl group, analkylacyl group, an arylacyl group, an alkylenylacyl group, and analkynylacyl group, wherein n is 1, 2, or 3, wherein p is 0, 1 or 2,wherein n+p≦3, and wherein any two R₁-R₃₄ in the same molecule may belinked to form a three- to eight-membered cyclic group.

A third aspect of the present invention provides a method forstabilizing a volatile alkylating agent, comprising: providing anon-aqueous flowable ointment or cream, wherein the non-aqueous flowableointment or cream does not include petrolatum or ethanol;reconsitituting an HX salt of the volatile alkylating agent in anhydroussolvent; combining with mixing the non-aqueous flowable ointment orcream and the HX salt of the volatile alkylating agent.

A fourth aspect of the present invention provides an apparatus having awall around a compartment, wherein the wall is made of a material thatis impervious to a mixture of a pharmaceutically acceptable nitrogenmustard.HCl and a non-aqueous vehicle or carrier that does not includepetrolatum or ethanol.

BRIEF DESCRIPTION OF THE DRAWINGS

The features of the invention are set forth in the appended claims. Theinvention itself, however, will be best understood by reference to thefollowing detailed description of an illustrative embodiment when readin conjunction with the accompanying drawings, wherein:

FIG. 1 depicts a front cross-sectional view of an apparatus having acompartment partially enclosed by a wall, in accordance with embodimentsof the present invention;

FIG. 2 depicts the apparatus having plugs mechanically sealed to closean opening in the wall, in accordance with embodiments of the presentinvention; and

FIG. 3 depicts the apparatus wherein the heat seals have been serratedto permit easy removal of the plugs, in accordance with embodiments ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, patients having MF topically treated with NitrogenMustard compounded into a polypropylene glycol (PPG, molecular weightfrom about 300 to about 2500), propylene glycol (PG), polyethyleneglycol(PEG, molecular weight from about 100 to about 1000) or ethylene glycolointment or cream showed no evidence of any systemic toxicities.

Table 1 below provides a summary of topical treatment of patients havingMF with nitrogen mustard in propylene glycol (PG), including responserates and toxicities.

TABLE 1 Topical Nitrogen Mustard In Mycosis Fungoides (MF): Summary OfClinical Outcomes & Toxicities. F/U % HYPERSENSITIVITY % SYSTEMIC #PTS(YRS) VEHICLE DOSE % CR % PCR REACTIONS TOXICITIES* 14 <1 PG 10 mg % 36%42% 7% 0% Topically Applied Once Daily *Systemic toxicities monitored byserial History & Physicals and laboratory studies. Abbreviations: PTS =patients studies; F/U = follow-up; CR = complete response; PG =propylene glycol, PCR = partial response; NR = not reportedSystemic Absorption

There is no evidence of any clinically significant systemic absorptionof topically applied Nitrogen Mustard. No systemic toxicities frompercutaneous absorption have been observed in long-term topical NitrogenMustard use in MF.

Genetic toxicity—No genetic toxicity has been observed with the use oftopical Nitrogen Mustard application. This is best documented in a studythat demonstrated no effect on sister-chromatid exchanges in theperipheral blood lymphocytes of CTCL-MF patients assayed before andafter topical Nitrogen Mustard treatment.

Bone Marrow Suppression—No evidence of bone marrow suppression (anemia,leukoopenia or thrombocytopenia) has reported with long term use oftopical Nitrogen Mustard, based on serial monitoring of the completeblood count.

Heptatotoxicity—No evidence of hepatotoxicty has reported with long termuse of topical NM, based on serial monitoring of peripheral blood liverfunction tests.

Nephrotoxicity—No evidence of nephrotoxicity has reported with long termuse of topical Nitrogen Mustard, based on serial monitoring ofperipheral blood renal function tests.

Environmental Contamination

Minimal evidence of environmental contamination has also beendemonstrated with topical Nitrogen Mustard use.

Cutaneous Side Effects

Hyperpigmentation—resulting from the direct melanogenic effects ofNitrogen Mustard, has been reported in a large percentage of treatedpatients. The hyperpigmentation is reversible and decreases gradually inmost patients even if topical therapy is continued.

Contact dermatitis—is a common complication of topical Nitrogen Mustardapplication. An irritant contact dermatitis is most common and can beseen in up to 25% of individuals using topical Nitrogen Mustardointment, particularly if used in sensitive areas such as the face orskin folds. Allergic contact dermatitis is also observed with topicalNitrogen Mustard use.

Immediate-type (urticarial) reactions—are rare.

Allergic contact dermatitis—from delayed-type hypersensitivity (DTH)reactions is more common and appears to be dose dependent. Higherconcentrations of aqueous preparations are associated with a DTHfrequency of 10-67%. Desensitization with lower concentrations ofNitrogen Mustard has been successfully employed in patients with DTHreactions to Nitrogen Mustard. The use of a lower concentration ointmentpreparation dramatically reduces the incidence DTH reactions. StanfordUniversity reported 0% DTH reactions in patients using Nitrogen Mustardointment for the first time and an 8% frequency of DTH in patients witha previous history of HN hypersensitivity, in their series utilizing anNitrogen Mustard ointment preparation.

Pediatric Use

Topical Nitrogen Mustard has been reported to be used in children andadolescences (<18 years) without any significant differences intoxicities than in adults.

Use in Pregnancy

Despite the lack of evidence of percutaneous absorption of topicalNitrogen Mustard, the use of topical Nitrogen Mustard has historicallybeen avoided in pregnant and nursing women.

Cutaneous Carcinogenesis

There are no reports of a significantly increased incidence of squamouscell carcinoma (SCC) of the skin with prolonged use of topical NitrogenMustard. Several groups have reported an approximately 10% (4%-14%)frequency of SCC in CTCL-MF patients using topical Nitrogen Mustard andsuggest a potential risk of epidermal carcinogenesis. Theseretrospective studies, however, do not account for confoundingvariables, such as CTCL-MF associated risk for second malignancies,prior therapies (e.g. radiation therapy to the skin), and do not haveadequate control groups.

In normal DNA strand replication, a DNA strand havingdeoxyribonucleosides, wherein each deoxyribonucleoside may include abase adenine (A), thymine (T), cytosine (C) and guanine (G), replicatesby linking each deoxyribonucleoside on the strand with anotherdeoxyribonucleoside, wherein typical linking occurs between adenine (A)and thymine (T), forming an A-T linkage and between cytosine (C) andguanine (G), forming a C-G linkage between the original DNA strand andits replicated DNA strand.

Nitrogen Mustard alkylating agents may act as anti-cancer agents byimpairing natural DNA strand replication of cancer cells, allowingunnatural base-base linkages such as a guanine (G) base linking toanother guanine (G) base if the particular Nitrogen Mustard alkylatingagents are bifunctional alkylators. Hereinafter, bifunctional alkylatorsare Nitrogen Mustards having at least two 2-chloroethyl side chains,e.g. bis-(2-chloroethyl)methyl amine, such as structure I of Reaction 1,infra.

Reaction 1, infra, depicts a reversible reaction, represented by forwardreaction 1a and reverse reaction 1b in Reaction 1, in which a NitrogenMustard alkylating agent having a 2-chloroethyl side chain, e.g.,bis-(2-chloroethyl)methylamine, represented by structure I, infra, mayundergo an intramolecular cyclization, resulting in formation of ahighly reactive ethyleniminium intermediate (aziridinium cation),represented by a structure II, infra. A concentration of the aziridiniumcation, II, infra, may be in equilibrium with a concentration of theNitrogen Mustard, I, infra, wherein the equilibrium constantK_(eq(1a,1b)) may be represented by a ratio of a rate k_(1a), of theforward reaction 1a, to a rate k_(1b), of the reverse reaction 1b.

In structure I, a carbon atom bonded to chlorine may initially have apartial positive charge, δ+, and a chlorine atom may initially have apartial negative charge, δ−. In Reaction I, an unshared pair ofelectrons of nitrogen may form a covalent bond to the carbon having δ+,releasing the chlorine atom as chloride, and forming structure II.

Structure II, supra, may undergo nucleophilic attack by an electrondonor, i.e., a nucleophile, resulting in alkylating the nucleophile.Reaction with the nucleophile guanine (G), structure III, shown inReaction 2, supra, at position N-7 of the guanine (G) occurs to thegreatest extent. Other sites on guanine (G), and other DNA bases such asadenine (A), cytosine (C) and thymine (T), and phosphate oxygens alsocan be alkylated. Hereinafter, structure III represents allstereoisomers and racemates of the deoxyribonucleoside having any DNAbase.

Reaction 2, supra, results in forming the alkylated deoxyribonucleoside,structure IV. In Reaction 2 supra, position N-7 of the guanine (G) baseof the deoxribonucleoside, represented in structure III, maynucleophilically attack the aziridinium ring, structure II, that mayhave been formed by the intramolecular cyclization represented byReaction 1, supra, resulting in alkylating position N-7 of the guanine(G) base of structure III. Hereinafter, structure IV represents allstereoisomers and racemates of the deoxyribonucleoside having any DNAbase.

Alkylating agents have four actions on nucleic acids. First of all, theagent may cause crosslinking of DNA strands which interferes with DNAand RNA synthesis. This is thought to be the most important reason forthe cytotoxic effect of alkylating agents. Secondly, the agent may alterthe “side chain groups” of the nucleotide base ring which would lead toabnormal base pairing and point mutations in the synthesized DNA and RNAchains. Thirdly, the alkylating agent may split the base ring from thenucleotide which again interrupts proper DNA and RNA synthesis. Finally,the alkylating agent may break the ring structure of a nucleotide basewhich would prevent base pairing during DNA and RNA synthesis.

In normal DNA strand replication, a DNA strand consisting ofdeoxyribonucleosides, wherein each deoxyribonucleoside may include abase adenine (A), thymine (T), cytosine (C) and guanine (G), replicatesby linking each deoxyribonucleoside on the strand with anotherdeoxyribonucleoside, wherein typical linking occurs between adenine (A)and thymine (T), forming an A-T linkage and between cytosine (C) andguanine (G), forming a C-G linkage between the original DNA strand andits replicated DNA strand.

Nitrogen Mustard alkylating agents may act as anti-cancer agents byimpairing normal DNA strand replication, allowing abnormal base-baselinkages such as a guanine (G) base linking to another guanine (G) baseif the particular Nitrogen Mustard alkylating agents are bifunctionalalkylators. Hereinafter, bifunctional alkylators are Nitrogen Mustardshaving at least two 2-chloroethyl side chains, e.g.bis-(2-chloroethyl)methyl amine, structure I, supra.

In Reaction 2, supra, one of the 2-chloroethyl side chains of thedeoxyribonucleoside represented by the structure IV has alkylated theguanine (G) base of the structure III. In reversible Reaction 3, infra,the remaining 2-chloroethyl side chain of the deoxyribonucleoside of thestructure IV has also undergone an intramolecular cyclization, resultingin formation of deoxyribonucleoside V, having the highly reactiveaziridinium ring.

Reaction 4, infra, depicts the abnormal linking of thedeoxyribonucleoside V, having a guanine (G) base and the activatedaziridinium ring, with another deoxyribonucleoside III, also having aguanine (G) base, forming an abnormal guanine-guanine (G-G) link in theproduct, represented by the structure VI. Hereinafter, structure VIrepresents all stereoisomers and racemates of the product from couplingtwo molecules of the deoxyribonucleoside represented by structure III atthe N-7 position with the bifunctional alkylating Nitrogen Mustardrepresented by the structure II, supra.

A highly unstable nature and extremely short duration of action of theNitrogen Mustards in the presence of water may result because water maydecompose the highly reactive ethyleniminium intermediate (aziridiniumcation), represented by the structure II, in Reaction 1, supra,replacing the chlorine atom on the 2-chloroethyl side chains of theNitrogen Mustard by an OH group. The Nitrogen Mustards are said to behighly unstable and have an extremely short duration of action becausethey may react with water, resulting in replacement of one or both ofthe chlorine atoms by a hydroxyl (OH) group. Replacement of the chlorineatoms may block formation of the aziridinium cation and therefore mayprevent the Nitrogen Mustards from acting as alkylating agents of, forexample, the N-2 position of the guanine base of DNA. Reaction 5illustrates competing equilibrium reactions, 1a and 1b and 5a and 5b. InReactions 1a and 1b, a free form of the Nitrogen Mustard, structure I,may be in equilibrium with the aziridium ion II, as described forReaction 1, supra. The equilibrium constant for Reactions 1a and 1b hasbeen described as K_(eq(1a,1b)), supra. In like manner, the equilibriumconstant for Reactions 5a and 5b, K_(eq(5a,5b)) may be expressed as theratio of the concentration of the HX salt, IX, to the product of theconcentration of the free form of the Nitrogen Mustard, structure I andthe concentration of HX. Therefore, in an embodiment, there may be anequilibrium concentration of aziridinium cation represented by the ratioof K_(eq(1a,1b)) to K_(eq(5a,5b)), even when the Nitrogen Mustard hasbeen stabilized by converting the free base form of the NitrogenMustard, as represented by structure I, infra, as illustrated byReaction 5, infra, to its HX salt, as represented by the structure IX.Therefore, the N-2 position of the guanine base of DNA, structure III inReactions 2-4 may be alkylated by the HX salt IX, as in Reaction 5,infra, because the concentration of the aziridinium cation in Reaction5, infra, may be a real positive number, equal to K_(eq(1a,1b)) toK_(eq(5a,5b)). Hereinafter, the free base form of the Nitrogen Mustardis any non-salt form of the Nitrogen Mustard, wherein a lone pair ofelectrons on the nitrogen atom may be available for forming theaziridinium ion, II, as in Reaction 1, supra. In embodiments of thepresent invention, the aziridinium cation, Structure II, supra, mayundergo nucleophilic attack by an electron donor, resulting inalkylating the nucleophile. For example, reaction with the nucleophileguanine (G), structure III, shown in Reaction 2, supra, at position N-7of the guanine (G) occurs to the greatest extent. Other sites on guanine(G), and other DNA bases such as adenine (A), cytosine (C) and thymine(T), and phosphate oxygens also can be alkylated.

The inventors disclose that oxygen of primary alcohols often arenucleophiles and therefore may have a disadvantageous effect on the useof the free base or the pharmaceutically acceptable HX salt IX, as inreaction 5, infra, because the free base of the nitrogen mustard or thepharmaceutically acceptable HX salt IX is consumed in the undesirableside reaction in which the nucleophile is alkylated by the free base ofthe nitrogen mustard or the pharmaceutically acceptable HX salt IX,instead of being available to act as an anti-cancer agent against T-Celllymphoma, for example, by impairing normal DNA strand replication.Hereinafter, pharmaceutically acceptable HX salt IX, as in reaction 5,infra, refers to salt forms that are pharmacologically acceptable andsubstantially non-toxic to the subject being treated with the compoundof the invention. Therefore, secondary and tertiary alcohols, amines,amino alcohols having from 1 to 20 carbon atoms are preferred overprimary alcohols having from 1 to 20 carbon atoms in formulations of thefree base of the nitrogen mustard or the pharmaceutically acceptable HXsalt IX, when a pharmaceutically acceptable inert ingredient, i.e., apharmaceutically acceptable excipient, may be needed to promotesolubilization of the free base of the nitrogen mustard or thepharmaceutically acceptable HX salt IX in the non-aqueous vehicle orcarrier that does not include petrolatum or ethanol.

Ethyl alcohol is not used to dissolve the nitrogen mustard or its HXsalt because it is a nucleophile that degrades the nitrogen mustard orits HX salt by promoting loss of chlorine. Isopropyl, cetyl, stearyl,cetearyl, or lanolin alcohol are preferred pharmaceutically acceptableexcipients for dissolving or taking up the nitrogen mustard or its HXsalt. Alternatively, for example, for topical formulations,pharmaceutically acceptable excipients may comprise solvents,emollients, humectants, preservatives, emulsifiers, and pH agents.Suitable solvents include acetone, glycols, polyurethanes, and othersknown in the art. Suitable emollients include mineral oil, propyleneglycol dicaprylate, lower fatty acid esters, lower alkyl ethers ofpropylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol,stearic acid, wax, and others known in the art. Suitable humectantsinclude glycerin, sorbitol, and others known in the art. Suitableemulsifiers include glyceryl monostearate, glyceryl monoleate, stearicacid, polyoxyethylene cetyl ether, polyoxyethylene cetostearyl ether,polyoxyethylene stearyl ether, polyethylene glycol stearate, propyleneglycol stearate, and others known in the art. Suitable pH agents includehydrochloric acid, phosphoric acid, diethanolamine, triethanolamine,sodium hydroxide, monobasic sodium phosphate, dibasic sodium phosphate,and others known in the art. Alternatively, pH agents include from about1 percent by weight to about 15 percent by weight acetic acid, citricacid or lactic acid. Suitable preservatives include benzyl alcohol,sodium benzoate, parabens, and others known in the art.

The inventors disclose that polyethylene glycol (PEG), ethylene glycol(EG), polypropylene glycol (PPG), propylene glycol (PG) and thediethylene glycol monosubstituted ether (DGMSE) are usefulpharmaceutically acceptable excipients. The polyethylene glycol (PEG),ethylene glycol (EG), polypropylene glycol (PPG), propylene glycol (PG)and the diethylene glycol monosubstituted ether (DGMSE) that mayhydrogen bond to trace nucleophiles that may be contaminants in thepharmaceutically acceptable excipients, thereby reducing thenucleophilic strength of the trace nucleophiles. Therefore diethyleneglycol monosubstituted ether (DGMSE) or silicones such as dimethicone orcyclomethicone are useful as pharmaceutically acceptable excipients topromote dissolution of the free base of the nitrogen mustard or the HXsalt IX, infra, in formulations of the free base of the nitrogen mustardor the pharmaceutically acceptable HX salt IX, infra.

In embodiments of the present invention, pharmaceutically acceptable HXsalts of the Nitrogen Mustard, structure IX, infra, are more stable andof longer activity duration than their respective free bases, asmeasured by an effective alkylating activity of the pharmaceuticallyacceptable HX salts of the Nitrogen Mustard, structure IX, infra, in thenon-aqueous vehicle or carrier that does not include petrolatum orethanol, wherein an effective alkylating activity of thepharmaceutically acceptable HX salts in the non-aqueous vehicle orcarrier that does not include petrolatum or ethanol after three (3)years is equivalent to the effective alkylating activity of the freebase form of the respective Nitrogen Mustards, structure I, after 3months in the non-aqueous vehicle or carrier that does not includepetrolatum or ethanol. The non-aqueous vehicle or carrier that does notinclude petrolatum or ethanol in formulations of the nitrogen mustardfree base or the pharmaceutically acceptable HX salts, structure IX,infra, does not include any grade of white or yellow petrolatumrecognized in the art as suitable for human application. The non-aqueousvehicle or carrier that does not include petrolatum or ethanol does notinclude material commercially available as Penreco Snow White Pet USP informulations of the nitrogen mustard free base or the pharmaceuticallyacceptable HX salts, structure IX, infra. The non-aqueous vehicle orcarrier that does not include petrolatum or ethanol does not includehydrocarbon mixtures formulated with mineral oils in combination withparaffin waxes of various melting points in formulations of the nitrogenmustard free base or the pharmaceutically acceptable HX salts, structureIX, infra. The non-aqueous vehicle or carrier that does not includepetrolatum or ethanol does not include lipophilic emollient selectedfrom the group consisting of: petrolatum; esters of fatty acids.Hereinafter, the effective alkylating activity of the pharmaceuticallyacceptable HX salts, structure IX, infra, in the non-aqueous vehicle orcarrier that does not include petrolatum or ethanol is equivalent to theeffective alkylating activity of the free base form of the respectiveNitrogen Mustards in the non-aqueous vehicle or carrier that does notinclude petrolatum or ethanol when a weight percent of thepharmaceutically acceptable HX salt, structure IX, infra, in thenon-aqueous vehicle or carrier that does not include petrolatum orethanol is essentially equal to the weight percent of the respectivefree base of the Nitrogen Mustard, structure I in the non-aqueousvehicle or carrier that does not include petrolatum or ethanol.

In embodiments of the present invention, use of the pharmaceuticallyacceptable HX salt, structure IX, infra, of the Nitrogen Mustard in thenon-aqueous vehicle or carrier that does not include petrolatum orethanol may preserve the effective alkylating activity by reducing itsvolatility compared to that of the free base form, sincepharmaceutically acceptable HX salts of Nitrogen Mustards generally havelower vapor pressures than their corresponding free base forms.

Reaction represented by arrow 5c, infra, illustrates formation of thestabilized Nitrogen Mustard.HX compositions of the present inventionthat have been stabilized by converting said free form highly reactiveNitrogen Mustard alkylating agents to pharmaceutically acceptable HXsalts by reaction of the Nitrogen Mustard with HX.

In an embodiment, X⁻ may advantageously be halide, such as Cl⁻, Br⁻, I⁻or HSO₄ ⁻ or NO₃, wherein HX may be respectively, HCl, HBr, HI, orH₂SO₄, or HNO₃. Alternatively pharmaceutically acceptable HX saltsinclude conventional acid-addition salts or base-addition salts formedfrom suitable non-toxic organic or inorganic acids or inorganic bases.Exemplary acid-addition salts include those derived from inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, sulfamic acid, phosphoric acid, and nitric acid, and those derivedfrom organic acids such as p-toluenesulfonic acid, methanesulfonic acid,ethane-disulfonic acid, isethionic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, 2-acetoxybenzoic acid, acetic acid, phenylacetic acid,propionic acid, glycolic acid, stearic acid, lactic acid, malic acid,tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, glutamicacid, salicylic acid, sulfanilic acid, and fumaric acid. Exemplarybase-addition salts include those derived from ammonium hydroxides(e.g., a quaternary ammonium hydroxide such as tetramethylammoniumhydroxide), those derived from inorganic bases such as alkali oralkaline earth-metal (e.g., sodium, potassium, lithium, calcium, ormagnesium) hydroxides, and those derived from non-toxic organic basessuch as basic amino acids.

Hereinafter, the pharmaceutically acceptable Nitrogen Mustard or thepharmaceutically acceptable HX salt of the Nitrogen Mustard is an activepharmaceutical ingredient (API). In an embodiment, the API may beprovided as a 10:1 weight ratio of NaCl:API. Alternatively the weightratio of NaCl to the API may be from about 100:0.01 to 0.01:100.Alternatively the API may be formulated into any solid mixture havingone or more of the above mentioned pharmaceutically acceptable HX salts.The inventors disclose that in theory the API, as the HX salt isstabilized in a salt matrix because the salt matrix and the HX salt ofthe API are both ionic.

One embodiment of the present invention, is a method for treating aperson with a skin disorder, comprising: topically applying to theaffected skin a pharmaceutically acceptable Nitrogen Mustard or apharmaceutically acceptable HX salt of the Nitrogen Mustard, wherein theNitrogen Mustard or the pharmaceutically acceptable HX salt of theNitrogen Mustard is in a non-aqueous vehicle or carrier that does notinclude petrolatum or ethanol, wherein the Nitrogen Mustard isrepresented by the following structures:

In an embodiment, each R₁, R₂, R₃ . . . R₃₄ (R₁-R₃₄) is independentlyselected from the group consisting of a hydrogen atom, a linear alkylgroup having 1-6 carbon atoms, a branched alkyl group having 2-12 carbonatoms, a cycloalkyl group having 3-17 carbon atoms, a fluorinated linearalkyl group having 2-12 carbon atoms, a fluorinated branched alkyl grouphaving 2-12 carbon atoms, a fluorinated cycloalkyl group having 3-17carbon atoms, an aryl group, an aralkyl group, an alkaryl group, acycloalkyl group, a bicycloalkyl group, an alkenyl group, an alkalkenylgroup, an alkenylalkyl group, an alkynyl group, an alkalkynyl group, analkynylalkyl group, a trifluoropropyl group, a cyanopropyl group, anacryloyl group, an arylacryloyl group, an acryloylaryl group, analkylacyl group, an arylacyl group, an alkylenylacyl group, and analkynylacyl group.

In an embodiment, n is 1, 2, or 3.

In an embodiment, p is 0, 1, or 2 and n+p≦3.

In an embodiment, any two R₁-R₃₄ in the same molecule may be linked toform a three- to eight-membered cyclic group.

In an embodiment, the Nitrogen Mustard is advantageously selected fromthe group consisting of bis-(2-chloroethyl)ethylamine,bis-(2-chloroethyl)methylamine, and tris-(2-chloroethyl)amine, andcombinations thereof. Hereinafter, structures VII, VIII, IX and X(XI-XIV) may represent all racemic forms and stereoisomers wherein saidcompounds may be capable of optical activity.

Alternatively, in an embodiment, the Nitrogen Mustard may beadvantageously derived from a Nitrogen Mustard prodrug represented bythe following structures:

In an embodiment, each R₃₅, R₃₆, R₃₇ . . . R₇₈ (R₃₅-R₇₈) isindependently selected from the group consisting of a hydrogen atom, alinear alkyl group having 1-6 carbon atoms, a branched alkyl grouphaving 2-12 carbon atoms, a cycloalkyl group having 3-17 carbon atoms, afluorinated linear alkyl group having 2-12 carbon atoms, a fluorinatedbranched alkyl group having 2-12 carbon atoms, a fluorinated cycloalkylgroup having 3-17 carbon atoms, an aryl group, an aralkyl group, analkaryl group, a cycloalkyl group, a bicycloalkyl group, an alkenylgroup, an alkalkenyl group, an alkenylalkyl group, an alkynyl group, analkalkynyl group, an alkynylalkyl group, a trifluoropropyl group, acyanopropyl group, an acryloyl group, an arylacryloyl group, anacryloylaryl group, an alkylacyl group, an arylacyl group, analkylenylacyl group, and an alkynylacyl group.

In an embodiment, any two R₁-R₅₇ in the same molecule may be linked toform a three- to eight-membered cyclic group.

In an embodiment, each X group is a linking group selected from thegroup consisting of a linear or branched alkylene having 1 to 7 carbonatoms, a cycloalkylene having 3 to 17 carbon atoms, analkylcycloalkylene having 4 to 20 carbon atoms, a cycloalkylalkylenehaving 4 to 20 carbon atoms, an arylene, having 4 to 30 carbon atoms, analkylarylene, having 4 to 30 carbon atoms, an arylalkylene, having 4 to30 carbon atoms, and combinations thereof,

In an embodiment, each Ar group is a bifunctional aromatic linkinggroup, wherein each Ar is selected from the group consisting of anarylene group, a substituted arylene group and/or a heteroarylene group.

Compounds represented by structures XI, XII, . . . XIV (XI-XIV) may beprodrug candidate forms of the Nitrogen Mustards, because they can bemetabolized in vivo to generate the active Nitrogen Mustard.Hereinafter, a “prodrug” is a precursor (forerunner) of the activeNitrogen Mustard. A prodrug may undergo chemical conversion by metabolicprocesses to the parent drug, thus becoming an active Nitrogen Mustard.Hereinafter, structures XI, XII, . . . XIV (XI-XIV) may represent allracemic forms and stereoisomers, wherein said compounds may be capableof optical activity.

For example, phosphatase and phosphamidase enzymes may hydrolyze the P—Nbond of structure XI, supra,e.g., cyclophosphamide, structure XIA, infraor ifosphamide, structure XIB, infra, resulting in an intermediatealdophosphamide, which may nonenzymatically break down to a bifunctionalphosphoramide mustard. In an embodiment, cyclophosphamide, structureXIA, supra or ifosphamide, structure XIB, supra may be oxidativelyactivated by cytochrome P-450

In an embodiment, structure XII, supra, e.g., Chlorambucil, structureXIIA, infra, may be a bifunctional alkylating agent of the nitrogenmustard type.

Structure XII may be cell cycle-phase nonspecific, although it also maybe cytotoxic to nonproliferating cells. Activity may occur as a resultof formation of an unstable ethylenimmonium ion, which alkylates orbinds with many intracellular molecular structures, including nucleicacids. Its cytotoxic action may be primarily due to cross-linking ofstrands of DNA, which inhibits nucleic acid synthesis.

In an embodiment structure, XIII, supra, e.g.,4-Bis(2-chloroethyl)amino-L-phenylalanine, Melphalan, structure XIIIA,infra, may be a bifunctional alkylating agent of the nitrogen mustardtype.

Like the nitrogen mustard prodrugs of structure XII, prodrugs ofstructure XIII may be cell cycle-phase nonspecific, although they alsomay be cytotoxic to nonproliferating cells.

In an embodiment, structure XIV, supra, e.g., uracil mustard, structureXIVA, infra, may be a bifunctional alkylating agent of the nitrogenmustard type.

In an embodiment, the pharmaceutically acceptable HX salt of theNitrogen Mustard may be advantageously selected from the groupconsisting of Nitrogen Mustard.HCl, Nitrogen Mustard.H₂SO₄, NitrogenMustard.HNO₃, Nitrogen Mustard.H₂SO₄, Nitrogen Mustard.HBr, NitrogenMustard.HI and combinations thereof.

In an embodiment, an ingredient of the non-aqueous vehicle or carrierthat does not include petrolatum or ethanol may be polyethylene glycol(PEG) or ethylene glycol (EG), polypropylene glycol (PPG) or propyleneglycol (PG), diethylene glycol monosubstituted ether (DGMSE),HOCH₂CH₂OCH₂CH₂OR₇₉(HO(CH₂CH₂O)₂R₇₉), wherein R₇₉ is selected from thegroup consisting of a linear alkyl group having 1-6 carbon atoms, abranched alkyl group having 2-12 carbon atoms, a cycloalkyl group having3-17 carbon atoms, a fluorinated linear alkyl group having 2-12 carbonatoms, a fluorinated branched alkyl group having 2-12 carbon atoms, afluorinated cycloalkyl group having 3-17 carbon atoms, an aryl group, anaralkyl group, an alkaryl group, a cycloalkyl group, a bicycloalkylgroup, an alkenyl group, an alkalkenyl group, an alkenylalkyl group, analkynyl group, an alkalkynyl group, an alkynylalkyl group, atrifluoropropyl group, a cyanopropyl group, an acryloyl group, anarylacryloyl group, an acryloylaryl group, an alkylacyl group, anarylacyl group, an alkylenylacyl group and an alkynylacyl group.

In an embodiment, each ingredient of the non-aqueous vehicle or carrierthat does not include petrolatum or ethanol may be selected from thegroup consisting of Ethoxy Diglycol Reagent, Hydroxypropylcellulose,buffer gel, Menthol Crystals USP, Butylated Hydroxytoluene NF, GlycerinUSP, Edetate Disodium USP, Decyl Methyl Sulfoxide, Kris-Ester 236 andcombinations thereof.

Buffer gel is selected from the group consisting of 2-Propenoic acid,Acrylate, Acrylic acid, Propenoate, Vinylformic acid, Acroleic acid,Ethylenecarboxylic acid, Propenoic acid, CH2═CHCOOH, Propene acid,Kyselina akrylova, Glacial acrylic acid, Ethylenecarboxylic acid, Acideacrylique [French], Acido acrilio [Spanish], Glacial acrylic acid,Kyselina akrylova [Czech], Propene acid, 2-Propenoic acid, homopolymer,Acrylic acid homopolymer, Acrylic acid polymer, Acrylic acid resin,Acrylic polymer, Acrylic polymer resins, Acrylic resin, Acrysol A 1,Acrysol A 3, Acrysol A 5, Acrysol AC 5, Acrysol WS-24, Acrysol ase-75,Acrysol lmw-20X, Antiprex 461, Antiprex A, Arasorb 750, Arasorb S 100F,Arolon, Aron, Aron A 10H, Atactic poly(acrylic acid), CCRIS 3234,Carbomer, Carbomer 1342, Carbomer 910, Carbomer 910 [USAN], Carbomer 934[USAN], Carbomer 934p [USAN], Carbomer 940 [USAN], Carbomer 941 [USAN],Carbopol 1342, Carbopol 910, Carbopol 934, Carbopol 934P, Carbopol 940,Carbopol 941, Carbopol 960, Carbopol 961, Carbopol 971P, Carbopol 974P,Carbopol 980, Carbopol 981, Carboset 515, Carboset Resin No. 515,Carboxy vinyl polymer, Carboxypolymethylene, Carpolene, Colloids 119/50,Cyguard 266, Dispex C40, Dow Latex 354, G-Cure, Good-rite K 37,Good-rite K 702, Good-rite K 732, Good-rite K-700, Good-rite K727,Good-rite WS 801, Haloflex 202, Haloflex 208, Joncryl 678, Junlon 110,Jurimer AC 10H, Jurimer AC 10P, NSC 106034, NSC 106035, NSC 106036, NSC106037, NSC 112122, NSC 112123, NSC 114472, NSC 165257, Nalfloc 636,Neocryl A-1038, OLD 01, P 11H, P-11H, PA 11M, PAA-25, POLYACRYLIC ACID,Pemulen TR-1, Pemulen TR-2, Poly(acrylic acid), Polyacrylate,Polyacrylate elastomers, Polymer of 2-propenoic acid, cross-linked withallyl ethers of pentaerythritol, Polymer of 2-propenoic acid,cross-linked with allyl ethers of sucrose, Polymer of 2-propenoic acid,cross-linked with allyl ethers of sucrose or pentaerythritol, Polymer ofacrylic acid, cross-linked with allyl ethers of pentaerythritol, Polymerof acrylic acid, cross-linked with allyl ethers of sucrose orpentaerythritol, Polymer, carboxy vinyl, Polymerized acrylic acid,Polytex 973, Primal ASE 60, Propenoic acid polymer, R968, Racryl,Revacryl A 191 Rohagit SD 15, Sokalan PAS, Solidokoll N, Synthemul90-588, TB 1131, Tecpol, Texcryl, Versicol E 7, Versicol EB5, VersicolE9, Versicol K 11, Versicol S 25, Viscalex HV 30, Viscon 103, WS 24, WS801, XPA, 54182-57-9, 9007-20-9, CARBOMER, Carbomere [INN-French],Carbomero [INN-Spanish], Carbomerum [INN-Latin], Carbopol,Carboxypolymethylene, Carboxypolymethylene resin, 2-Propenoic acid,Acrylic acid, Acroleic acid, Ethylenecarboxylic acid, Propenoic acid,Vinylformic acid, CH2=CHCOOH, Propene acid, Kyselina akrylova,2-Propenoic acid, calcium salt, Acrylic acid, calcium salt, Calciumacrylate, Calcium diacrylate, acrylic acid, 2-propenoic acid,AIDS-209945, AIDS209945, Carbomer, Carbopol 934P, 2-Propenoic acid,2-methyl-, 2-hydroxyethyl ester, polymer with etheny-1-acetate and2-ethylhexyl 2-propenoate.

In an embodiment, pharmaceutically acceptable HX salts of the NitrogenMustard alkylating agents used in the treatment of skin disorders may bemore stable and have a longer duration of activity because thepharmaceutically acceptable HX salts of the Nitrogen Mustards may bemore resistant to attack by water than the respective free base form ofthe Nitrogen Mustard. In an embodiment, the pharmaceutically acceptableHX salts of the Nitrogen Mustard alkylating agents may be added to anon-aqueous vehicle or carrier that may not include petrolatum. In anembodiment, the use of pharmaceutically acceptable HX salts of theNitrogen Mustard alkylating agents and/or adding them to the non-aqueousvehicle or carrier that may not include petrolatum may result in greaterstability and longer duration of action in the treatment of skindisorders.

In an embodiment, the skin disorder is selected from the groupconsisting of psoriasis, eczema, actinic keratosis, lupus, sarcoidosis,alopecia, cutaneous T-Cell lymphoma, i.e., mycosis fungoides,lymphoreticular neoplasia, pleural and peritoneal effusions, cutaneousB-cell lymphoma, pseudolymphomas of the skin, squamous cell carcinoma,basal cell carcinoma, bronchogenic carcinoma, malignant melanoma,lymphosarcoma, chronic lymphocytic leukemia, polycythemia vera,lymphomatoid papulosis, Mucha-Habberman's disease (PLEVA), andcombinations thereof.

Methods of delivery, as in the step 10 of the method 1 comprise topicaladministration of the Nitrogen Mustard or Nitrogen Mustard.HCl to humansand animals of sterile solutions or suspensions, wherein the dosagecontains suitable quantities of an active ingredient. Topical solutionsor suspensions are incorporated in a slow release non-aqueous matrix foradministering transdermally. In an embodiment, a dosage for mammals maybe from about 0.0001 percent by weight to about 2.0 percent by weight ofthe active ingredient in the non-aqueous and non-petrolatum matrix perday. In another embodiment, the dosage for mammals may be from about0.015 percent by weight to about 0.04 percent by weight of the activeingredient in the non-aqueous and non-petrolatum matrix per day. In anembodiment, the dosage for mammals may be from about 0.015 to about0.030 percent by weight of the active ingredient in the non-aqueous andnon-petrolatum matrix per day. Hereinafter, topical administration meansapplying a drug to a localized area of the body or to the surface of abody part.

In embodiments of the present invention, a method for treating a personwith a skin disorder, comprising: topically applying the NitrogenMustard or Nitrogen Mustard.HCl to the affected skin. In an embodimentof the method, the non-aqueous vehicle or carrier that does not includepetrolatum or ethanol ameliorates skin irritation resulting from theNitrogen Mustard or its HX salt, by providing an effective dose of theNitrogen Mustard or Nitrogen Mustard.HCl. Hereinafter, “ameliorates”means to lessen pain and reduce skin irritation, resulting in making animprovement because skin irritation has been reduced. Hereinafter, aneffective dose of the Nitrogen Mustard or Nitrogen Mustard.HCl may besufficient to treat the skin having one of the aforementioned diseaseswithout causing hypersensitivity, as disclosed in Table 1, supra.

In embodiments of the present invention, a method for stabilizing avolatile alkylating agent, comprising: providing a non-aqueous flowableointment or cream, wherein the non-aqueous flowable ointment or creamdoes not include petrolatum or ethanol; reconsitituting an FIX salt ofthe volatile alkylating agent in anhydrous solvent that does not includeethanol; combining with mixing the non-aqueous flowable ointment orcream and the HX salt of the volatile alkylating agent. In anembodiment, in the method for stabilizing the Nitrogen Mustard orNitrogen Mustard.HCl, the HX salt of the Nitrogen Mustard is NitrogenMustard.HCl. In an embodiment of the method for stabilizing the NitrogenMustard or the Nitrogen Mustard.HCl, a duration of activity of theNitrogen Mustard or the HX salt of the Nitrogen Mustard is from about 3months to about 3 years.

In an embodiment, in the method for stabilizing the Nitrogen Mustard orthe Nitrogen Mustard.HCl, the non-aqueous flowable ointment or creamincludes polypropylene glycol (PPG), propylene glycol (PG) orpolyethylene glycol (PEG) or ethylene glycol (EG). In an embodiment, inthe method for stabilizing the Nitrogen Mustard or the NitrogenMustard.HCl, the non-aqueous flowable ointment or cream consistsessentially of Propylene Glycol, Ethoxy Diglycol Reagent,Hydroxypropylcellulose, Menthol Crystals USP, Butylated HydroxytolueneNF, Glycerin USP, Edetate Disodium USP, Decyl Methyl Sulfoxide, andKris-Ester 236.

In an embodiment, in the method for stabilizing the Nitrogen Mustard orthe Nitrogen Mustard.HCl, the Nitrogen Mustard or its HX salt isselected from the group consisting of bis-(2-chloroethyl)ethylamine,bis-(2-chloroethyl)methylamine, tris-(2-chloroethyl)amine, andcombinations thereof.

In an embodiment, the acceptable non-aqueous vehicle or carrier thatdoes not include petrolatum or ethanol for the purpose of this inventionmay be flowable non-aqueous pharmaceutical vehicle or carriers such ascreams or ointments that do not contain nucleophiles, e.g., water orethanol, that may decompose the Nitrogen Mustard or its HX salt,structure IX, as depicted in Reaction 5, supra. In an embodiment,suitable pharmaceutically acceptable carriers include Ethoxy DiglycolReagent, Hydroxypropylcellulose, Menthol Crystals USP, ButylatedHydroxytoluene NF, Glycerin USP, Edetate Disodium USP, Decyl MethylSulfoxide, Kris-Ester 236, Propylene glycol and Ethylene Glycol. In anembodiment, the polypropylene glycol (PPG), propylene glycol (PG),polyethylene glycol (PEG) or ethylene glycol (EG) may be from about 15to about 60 weight percent propylene glycol or ethylene glycol. Thenon-aqueous vehicle or carrier that does not include petrolatum orethanol may also contain adjuvants such as preserving, stabilizing,wetting, emulsifying agents and the like together with the sensitizer ofthis invention.

In an embodiment of the present invention, the sensitizers can also beused as adjunct therapy in combination with existing therapies, such ashyperthermia, in the management cancer treatment in patients havingcancer.

Example 1 Preparation of from About 0.001 to About 2.0Bis-(2chloroethyl)methylamine Hydrochloride, Structure IX, as Depictedin Reaction 5 Supra

The drug product formulation consists of a pharmaceutically acceptablenitrogen mustard hydrochloride in a topical ointment base that does notinclude petrolatum or ethanol. The components/compositions are providedin Table 2 that follows, assuming a batch size of 1 liter.

TABLE 2 Unit/Batch Composition Amount Ingredient per 100 ml PerBatch^(a) Percent PPG, PG, PEG or EG USP 15-60 ml 0.15-0.6 L 15-60%Ethoxy Diglycol Reagent 15-60 ml 0.15-0.6 L 15-60%Hydroxypropylcellulose NF 1500 0.75 gm 0.0075 kg 0.75% CPS MentholCrystals USP 0.08 gm 0.0008 kg 0.08% Butylated Hydroxytoluene NF 0.05 gm0.0005 kg 0.05% (BHT) Glycerin USP 12.75 ml 0.1275 L 12.75%  EdetateDisodium USP 0.05 gm 0.0005 kg 0.05% Decyl Methyl Sulfoxide 0.125 gm0.00125 kg 0.13% Kris-Ester 236 liquid 5 gm 0.05 kg 5.00% AlchoholAnydrous 100% SDA 2.175 ml 0.02175 L 2.18% 3ABis-(2-chloroethyl)methylamine 0.001-2.0 gm gm 0.00001-0.02 kg0.001-2.0%  HCl^(b) ^(a)Slight overages of the drug substances may beused as required to offset losses during manufacture. ^(b)Available fromMerck & Co., West Point, PA 19486.

Manufacturing

The drug product, e.g., having 0.001-2.0 percent by weight NitrogenMustard as Bis-(2chloroethyl)methylamnine.HCl, structure IX, as inReaction 5, supra, may be manufactured according to the followinggeneral procedure:

Preparation of the Ointment

-   1. All dry excipient ingredients are assembled and weighed out    according to the formula in Table 2 and placed in an appropriate    vessel. Hereinafter, an excipient is an inert substance which is    added to the free form of the nitrogen mustard or its    pharmaceutically acceptable HX salt to provide bulk. Hereinafter,    the dry excipient ingredients are indicated as being added as solid    weight, such as gram, i.e. gm.-   2. Particle sizes of the dry material are reduced to a uniform size    through tritration.-   3. Polypropylene glycol (PPG), propylene glycol (PG), polyethylene    glycol (PEG) or ethylene glycol (EG) from about 15 to about 60    percent by weight is then added via the principle of geometric    dilution to form a smooth paste. Once a smooth paste is achieved,    the propylene or ethylene glycol continues to be added until a    volume that retains a flow like quality is obtained.-   4. The entire contents are then transferred to a large beaker. A    spin bar is added and the beaker is placed on a magnetic stirring    plate and mixing is begun.-   5. As the mixture continues to spin, glycerin is added. While the    mixture spins, the original vessel is washed with from about 15 to    about 60 percent by weight ethoxy diglycol and the contents of the    vessel are added to the spinning mixture in the beaker.-   6. After the ethoxy diglycol is added, kris-ester is added to the    spinning mixture. This mixture then is spun for approximately one to    two hours. After the spinning is finished the mixture is covered and    left to sit over-night.-   7. The next day the mixture is mixed with a high shear mixer to a    uniform consistency with minimal to no air. Air and moisture may be    removed during mixing by applying a vacuum from about 0.01 to about    0.1 torr. The mixture is then brought to ambient pressure by adding    dry nitrogen.

Adding the Nitrogen Mustard

-   8. The appropriate concentration and amount of nitrogen mustard is    reconstituted with absolute alcohol (200 proof) then added to the    appropriate amount of non-aqueous vehicle or carrier, wherein the    non-aqueous vehicle or carrier does not include petrolatum or    ethanol and mixed to a uniform consistency via agitation for 60-90    seconds For example, in an embodiment, a concentration in mg/ml of    the pharmaceutically acceptable Nitrogen Mustard.HCl in the    non-aqueous vehicle or carrier that does not include petrolatum or    ethanol is advantageously from about 1 mg of Nitrogen Mustard.HCl    per 100 ml of non-aqueous vehicle to about 2000 mg of Nitrogen    Mustard.HCl per 100 ml of non-aqueous vehicle. In an embodiment, a    concentration in mg/ml of Nitrogen Mustard.HCl in a non-aqueous    vehicle or carrier that does not include petrolatum or ethanol is    advantageously from about 10 mg of Nitrogen Mustard.HCl per 100 ml    of non-aqueous vehicle or carrier that does not include petrolatum    or ethanol to about 40 mg of Nitrogen Mustard.HCl per 100 ml of    non-aqueous vehicle or carrier that does not include petrolatum or    ethanol. In an embodiment, a concentration in mg/ml of Nitrogen    Mustard.HCl used in a non-aqueous vehicle or carrier that does not    include petrolatum or ethanol is advantageously from about 15 mg of    Nitrogen Mustard.HCl per 100 ml of non-aqueous vehicle or carrier    that does not include petrolatum or ethanol to about 30 mg of    Nitrogen Mustard.HCl per 100 ml of non-aqueous vehicle or carrier    that does not include petrolatum or ethanol.-   9. This mixture is then poured into a 50 ml flip top plastic    cylinder and shipped to the appropriate patient.    Clean-Up

All vessels used in the process are placed in a Sodium Thiosulfateaqueous bath. Contents are left in the bath for 2 hours and then thewashed. The bath is then discarded by normal means. Note: SodiumThiosulfate reacts with nitrogen mustard to create an innocuous, safemixture that can be discarded by normal means.

Example 2 Preparation of from About 0.001 to About 2.0Bis-(2chloroethyl)methylamine Hydrochloride, Structure IX, as Depictedin Reaction 5 Supra

The drug product formulation consists of a pharmaceutically acceptablenitrogen mustard hydrochloride in a topical ointment base. Thecomponents/compositions are provided in Table 3 that follows, assuming abatch size of 1 liter.

TABLE 3 Unit/Batch Composition Parts per 100 Parts by Weight of FreeBase Nitrogen Ingredient^(a) Mustard or HX Salt Dimethicone orCyclomethicone 10-60 Diethylene Glycol Monosubstituted Ether, 10-16DGMSE, HO(CH₂CH₂O)₂R₇₉ Hydroxypropylcellulose NF 1500 CPS or 0-5 buffergel Menthol Crystals USP 0-1 Butylated Hydroxytoluene NF (BHT) 0-1Glycerin USP 1-2 Edetate Disodium USP   0-0.05 Decyl Methyl Sulfoxide   0-0.125 Kris-Ester 236 liquid 0-5 Anydrous Secondary or tertiaryAlcohol  1-20 API, e.g., Bis-(2-chloroethyl)methylamine 0.001-2.0 HCl^(b) C_(n)H_((2n+2))COOH, (n = 1-6) 0.01-15   ^(a)Slight overages ofthe drug substances may be used as required to offset losses duringmanufacture. ^(b)Available from Merck & Co., West Point, PA 19486.

The acceptable non-aqueous vehicle or carrier that does not includepetrolatum or ethanol for the purpose of this invention that is theflowable non-aqueous pharmaceutically acceptable non-aqueous vehicle orcarrier that does not include petrolatum or ethanol such as creams orointments do not contain nucleophiles, e.g., water or ethanol, that maydecompose the free form of the Nitrogen Mustard or its HX salt,structure IX, as depicted in Reaction 5, supra, may be dimethylpolysiloxane fluid such as dimethicone or cyclomethicone havingessentially no moisture content.

Hereinafter dimethicone means low viscosity silicones, low viscosity,i.e. from about 1 cps. to about 1,000 cps at 25° C.polydimethylsiloxanes, Hexamethyldisiloxane, CAS#107-46-0, pure silicone1 cSt, volatile silicone, volatile silicones, volatilepolydimethylsiloxanes, low temperature silicones, skin care silicone,skin care silicones, Octamethyltrisiloxane, CAS#107-51-7, CAS107-51-7,Decamethyltetrasiloxane, (CAS#141-62-8, DodecamethylpentasiloxaneCAS#141-63-9, trisiloxane, low viscosity dimethicone, volatiledimethicone, cosmetic dimethicone fluid, cosmetic base fluids, suntanlotion silicone, antiperspirant silicone, hair care silicone, lowsurface tension silicone, and low heat of vaporization silicone.

Hereinafter, cyclomethicone means cyclopentasiloxane, volatilepolydimethylcyclosiloxane, CAS 541-02-6, CAS#541-02-6, low surfacetension silicone, volatile silicone, D5 silicone, Dow Corning 245 fluid,DC 245 fluid, 245 silicone, skin cream silicone, antiperspirantsilicone, suntan lotion silicone, silicone for skin, skincare silicone,bodycare silicone, bath oil silicone, GE 1202, GE SF1202cyclopentasiloxane, D5 Cyclopentasiloxane, and D5 DecamethylcycloPentasiloxane.

Generally, dimethicone and cyclomethicone are dimethyl silicone oilswith good emollience, strong moisturization and humectant properties.Dimethicone and cyclomethicone have very low moisture content, as water,i.e. <0.1% by weight because they are methyl stopped instead of OHstopped polymers.

Manufacturing

The drug product, e.g., having 0.001-2.0 percent by weight NitrogenMustard as Bis-(2chloroethyl)methylamine.HCl, structure IX, as inReaction 5, supra, in Dimethicone or Cyclomethicone Ointment may bemanufactured according to the following general procedure:

Preparation of the Dimethicone or Cyclomethicone Ointment

-   a) All dry excipient ingredients are assembled and weighed out    according to the formula in Table 3 and placed in an appropriate    vessel.-   b) Particle sizes of the dry material are reduced to a uniform size    through tritration.-   c) Dimethicone or cyclomethicone from about 10 to about 60 percent    by weight is then added via the principle of geometric dilution to    form a smooth paste. Once a smooth paste is achieved, the    Dimethicone or cyclomethicone continues to be added until a volume    that retains a flow like quality is obtained.-   d) The entire contents are then transferred to a large beaker. A    spin bar is added and the beaker is placed on a magnetic stirring    plate and mixing is begun.-   e) As the mixture continues to spin, glycerin is added. While the    mixture spins, the original vessel is washed with from about 10 to    about 16 percent by weight ethoxy diglycol and the contents of the    vessel are added to the spinning mixture in the beaker.-   f) After the ethoxy diglycol is added, from about 0.01-15 percent by    weight of a pH modifier such as citric acid, lactic acid or    aliphatic acids having a formula C_(n)H_((2n+2))COOH, (n=1-6) is    added to the spinning mixture. This mixture then is spun for    approximately one to two hours. After the spinning is finished the    mixture is covered and left to sit over-night.-   g) The next day the mixture is mixed with a high shear mixer to a    uniform consistency with minimal to no air. Air and moisture may be    removed during mixing by applying a vacuum from about 0.01 to about    0.1 torr. The mixture is then brought to ambient pressure by adding    dry nitrogen.    Combining the Nitrogen Mustard and the Dimethicone or Cyclomethicone    Non-Aqueous Vehicle or Carrier that Does not Include Petrolatum or    Ethanol of Step g) Supra.

In one embodiment, a pharmaceutically acceptable nitrogen mustard.HClhaving an essentially completely uniform consistency may be formed byagitating for 60-90 seconds using a high shear mixer to mix 1) anappropriate amount of API having been be reconstituted with an anhydroussecondary or tertiary alcohol such as isopropyl alcohol, wherein ethanolhas been rigorously excluded from the anhydrous secondary or tertiaryalcohol such as isopropyl alcohol, and 2) the appropriate amount ofnon-aqueous vehicle or carrier that does not include petrolatum orethanol from step g), supra, wherein the non-aqueous vehicle or carrierdoes not include petrolatum or ethanol. For example, in an embodiment, aconcentration in mg/ml of the pharmaceutically acceptable NitrogenMustard.HCl in the non-aqueous vehicle or carrier that does not includepetrolatum or ethanol is advantageously from about 1 mg of NitrogenMustard.HCl per 100 ml of non-aqueous vehicle to about 2000 mg ofNitrogen Mustard.HCl per 100 ml of non-aqueous vehicle. In anotherembodiment, a concentration in mg/ml of the pharmaceutically acceptableNitrogen Mustard.HCl used in a non-aqueous vehicle or carrier that doesnot include petrolatum or ethanol is advantageously from about 10 mg ofNitrogen Mustard.HCl per 100 ml of non-aqueous vehicle or carrier thatdoes not include petrolatum or ethanol to about 40 mg of NitrogenMustard.HCl per 100 ml of non-aqueous vehicle or carrier that does notinclude petrolatum or ethanol. In another embodiment, a concentration inmg/ml of the pharmaceutically acceptable Nitrogen Mustard.HCl used in anon-aqueous vehicle or carrier that does not include petrolatum orethanol is advantageously from about 15 mg of Nitrogen Mustard.HCl per100 ml of non-aqueous vehicle or carrier that does not includepetrolatum or ethanol to about 30 mg of Nitrogen Mustard.HCl per 100 mlof non-aqueous vehicle or carrier that does not include petrolatum orethanol. This mixture may then be poured into a 50 ml flip top plasticcylinder and shipped to the appropriate patient.

The inventors disclose that lower volume containers having from about0.01 to about 0.2 ml, from about 0.1 to about 0.5 ml, or from about 0.1to about 1 ml may advantageously be used to provide from 1 to 10applications of the pharmaceutically acceptable Nitrogen Mustard.HClover a shorter period of use than the 50 ml flip top plastic cylinders,so that lower amounts of nucleophiles such as ambient water or otherambient nucleophiles such as methanol or ethanol may be introduced intothe lower volume containers than when the flip top plastic cylinder isopened to the ambient environment over a period of 100 to 1000applications. The inventors anticipate decreased decomposition of thefree form nitrogen mustard or its HX salt, structure IX, depicted inReaction 5, supra, when the pharmaceutically acceptable nitrogen mustardis contained in lower volume containers intended for from about 1 to 10applications. In theory, the chlorides of the free form of the nitrogenmustard or its HX salt may be displaced by nucleophilic attack, such asby water or ethanol, resulting in substitution of the Cl by an OH. Saiddecomposition of the free form of the nitrogen mustard or its HX saltmay be avoided by isolating the nitrogen mustard from traces of water,ethanol or other nucleophiles in the environment. An apparatus 20, asdepicted in FIG. 1, infra, depicts this smaller volume container.

FIG. 1 depicts a front cross-sectional view of the apparatus 20 forcontaining the pharmaceutically acceptable Nitrogen Mustard.HCl in thenon-aqueous vehicle or carrier that does not include petrolatum orethanol or the stabilized volatile alkylating agent or HX salt of thestabilized volatile alkylating agent, comprising: a compartment 25enclosed by a wall 31. The wall 31 comprises an outer surface 28 and aninner surface 23, ends 24 and 21, and opening 30. The first compartment25 may be charged with the essentially completely uniform mixture of thepharmaceutically acceptable nitrogen mustard.HCl, supra, through theopening 30. The opening 30 may be closed with plug 22. The plug 22 maybe made of the same material as the wall 31, or a lower melting plasticor wax material.

FIG. 2 depicts the apparatus 20, after forming heat seals 26 and 27 byheating the plug 22 and the ends 21 and 24 to their melting points,wherein heating physically and mechanically couples ends 21 and 24 toform mechanically strong heat seals 26 and 27.

FIG. 3 depicts the apparatus 20, after forming serated perforations 33and 34 in the plug 22 using a crimping tool or other appropriate devicefor forming serated perforations 33 and 34. The serated perforations 33and 34 weaken the heat seals 21 and 24 so that they become mechanicallyless strong, resulting in a tear line for removal of the plug 22 by thepatient seeking to apply the pharmaceutically acceptable nitrogenmustard.HCl to a diseased area or area for treatment. Alternatively, aperson could use an instrument having a sharp edge or blade, such asscissors, a razor blade or a knife, to pierce the plug 22, therebyrestoring the opening 30 in the wall 31 of the apparatus 20.

In one embodiment, a person wishing to apply the pharmaceuticallyacceptable nitrogen mustard.HCl to the diseased area or area fortreatment may remove plug 22 from the wall 31 of the apparatus 20,restoring the opening 30 in the wall 31. A person squeezing or applyingpressure to the wall 31 reduces the volume of the compartment 25,causing the pharmaceutically acceptable nitrogen mustard.HCl to flow outof the compartment 25 through the opening 30, thereby enabling topicalapplication of the pharmaceutically acceptable nitrogen mustard.HCl to adiseased area or area for treatment.

In one embodiment, a concentration of the pharmaceutically acceptableNitrogen Mustard.HCl in the non-aqueous vehicle or carrier that does notinclude petrolatum or ethanol in the compartment 25 is from about 1 mgof Nitrogen Mustard.HCl per 100 ml of non-aqueous vehicle to about 2000mg of Nitrogen Mustard.HCl per 100 ml of non-aqueous vehicle. In anotherembodiment, a concentration of the pharmaceutically acceptable NitrogenMustard.HCl in the non-aqueous vehicle or carrier that does not includepetrolatum or ethanol is from about 10 mg of Nitrogen Mustard.HCl per100 ml of non-aqueous vehicle or carrier that does not includepetrolatum or ethanol to about 40 mg of Nitrogen Mustard.HCl per 100 mlof non-aqueous vehicle or carrier that does not include petrolatum orethanol. In another embodiment, a concentration of the pharmaceuticallyacceptable Nitrogen Mustard.HCl in the non-aqueous vehicle or carrierthat does not include petrolatum or ethanol is advantageously from about15 mg of Nitrogen Mustard.HCl per 100 ml of non-aqueous vehicle orcarrier that does not include petrolatum or ethanol to about 30 mg ofNitrogen Mustard.HCl per 100 ml of non-aqueous vehicle or carrier thatdoes not include petrolatum or ethanol. An orifice or opening 30 may bemade by forming an opening in the outer wall 31, through which opening30 this mixture of the Nitrogen Mustard is then provided by prescriptionof a physician for treatment of the patient.

The outer wall 31 of apparatus 20 is impermeable or impervious to themixture of step g) or step 9), supra, and/or the reconstituted nitrogenmustard solutions. Hereinafter, “impermeable” or “impervious” means thewall 31 prevents the mixture of step g) or step 9), supra, and/or thereconstituted nitrogen mustard solutions to pass or diffuse through thewall 31. Hereinafter “impervious” means not admitting of passage of themixture of step g) or step 9), supra, and/or the reconstituted nitrogenmustard solutions through the wall 31 or the wall 31 being capable ofbeing affected by the mixture of step g) or step 9), supra, and/or thereconstituted nitrogen mustard solutions. The wall 31 may be made fromaluminum foil, plastic lined or resin coated aluminum foil, elastomericmaterials including ethylene/propylene copolymers,ethylene/ethylacrylate copolymers, ethylene/vinyl acetate copolymers,silicone elastomers, medical-grade polydimethylsiloxanes, neoprenerubber, polyisobutylene, chlorinated polyethylene, polyvinyl chloride,vinylchloride-vinyl acetate copolymer, polymethacrylate polymer(hydrogel), polyvinylidene chloride, poly(ethylene terephthalate), butylrubber, epichlorohydrin rubbers, ethylene-vinyl alcohol copolymer,ethylenevinyloxyethanol copolymer; silicone copolymers,polysiloxane-polycarbonate copolymers, polysiloxane-polyethyleneoxidecopolymers, polysiloxane-polymethacrylate copolymers,polysiloxane-polymethacrylate copolymers, polysiloxane-alkylenecopolymers polysiloxane-ethylene copolymers, polysiloxane-alkylenesilanecopolymers, polysiloxaneethylenesilane copolymers, cellulose polymers,methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose,cellulose esters, polycarbonates, polyesters, polytetrafluoroethylene,starches, gelatins, natural gums, synthetic gums, and combinationsthereof.

Clean-Up

All vessels used in the process are placed in a Sodium Thiosulfateaqueous bath. Contents are left in the bath for 2 hours and then thewashed. The bath is then discarded by normal means. Note: SodiumThiosulfate reacts with nitrogen mustard to create an innocuous, safemixture that can be discarded by normal means.

The foregoing description of the embodiments of this invention has beenpresented for purposes of illustration and description. It is notintended to be exhaustive or to limit the invention to the precise formdisclosed, and obviously, many modifications and variations arepossible.

1. A composition comprising: (a) bis-(2-chloroethyl)methylamine or apharmaceutically acceptable salt thereof; and (b) a pharmaceuticallyacceptable excipient, wherein the bis-(2-chloroethyl)methylamine orpharmaceutically acceptable salt thereof is present in an amount ofabout 0.001% to about 2.0% by weight of the composition; and thepharmaceutically acceptable excipient is a compound of the formulaHOCH₂CH₂OCH₂CH₂OR₇₉, wherein R₇₉ is a linear alkyl group having 1-6carbon atoms.
 2. The composition of claim 1, wherein thebis-(2-chloroethyl)methylamine is in the form of an acid-addition orbase-addition salt.
 3. The composition of claim 2, wherein theacid-addition salt is an HCl, HBr, H₁, H₂SO₄, or HNO₃ salt.
 4. Thecomposition of claim 1, wherein the pharmaceutically acceptableexcipient is a compound of the formula HOCH₂CH₂OCH₂CH₂OR₇₉, wherein R₇₉is a linear alkyl group having 2 carbon atoms (ethoxy diglycol reagent).5. The composition of claim 1, wherein thebis-(2-chloroethyl)methylamine or pharmaceutically acceptable saltthereof is present in an amount of about 0.01% to about 0.04% by weightof the composition.
 6. The composition of claim 3, wherein theacid-addition salt is an HCl salt.
 7. The composition of claim 6,wherein the pharmaceutically acceptable excipient is a compound of theformula HOCH₂CH₂OCH₂CH₂OR₇₉, wherein R₇₉ is a linear alkyl group having2 carbon atoms (ethoxy diglycol reagent).